Recent studies by the applicant have described dietary regulation of sympathoadrenal activity in the rat. Fasting decreases the activity of sympathetic nerves and the adrenal medulla unless hypoglycemia supervenes to stimulate selectively adrenal medullary secretion. Overfeeding, on the other hand, increases sympathoadrenal activity. Similar changes in sympathetic nervous system activity occur in normal mice. In two animal models of obesity, however, alterations in sympathoadrenal activity have been found. Gold thioglucose-treated obese mice fail to suppress sympathetic activity with fasting and consequently exhibit no effect of diet on sympathetic nervous system function. Ob/ob mice, a form of genetic obesity, display appropriate changes in sympathetic activity with diet, but with free access to food have significantly lower sympathetic nerve activity than control animals. The proposed studies seek to extend these observations to an animal model of nutritional obestity, the fat-fed mouse, and to explore possible central nervous system mechanisms for these alterations in sympathoadrenal regulation. Studies are planned to evaluate the effects of somatostatin, opiates and cold exposure on diet-induced changes in the activity of sympathetic nerves and the adrenal medulla in normal and obese mice. Experiments utilizing tracer norepinephrine (NE) to measure NE turnover will assess the effect of these pharmacologic and physiologic manipulations upon sympathetic activity in heart. Measurement of urinary catecholamine excretion and of adrenal epinephrine content will serve as an index of adrenal medullary activation. The long-term goal of this research is improved therapeutics of obesity based upon a better understanding of possible defects in the dietary regulation of sympathoadrenal activity. In addition the studies proposed here may have implications for the treatment of other diseases aggravated by chronic overfeeding.